Neoadjuvant Therapy As a Platform for Drug Development: Current Controversies and Regulatory Perspectives

November 16, 2015

This commentary addresses our perspectives from a regulatory standpoint, as well as some controversies related to the use of neoadjuvant therapy as a platform for drug development.

Neoadjuvant therapy for breast cancer, formerly limited to the treatment of patients with locally advanced tumors, has gradually become a common clinical practice. In this issue of ONCOLOGY, Dr. Santa-Maria and colleagues thoughtfully review the existing practice of neoadjuvant treatment; detail the considerations of a multidisciplinary approach; and discuss areas of controversy, including systemic treatment by tumor subtype, management of the axilla, and appropriate trial endpoints.[1] This commentary addresses our perspectives from a regulatory standpoint, as well as some controversies related to the use of neoadjuvant therapy as a platform for drug development. Clinical trials in the neoadjuvant setting have become common platforms from which to study new biomarkers, perform translational research, and assess drug activity more efficiently. The exponential increase in drug development in the neoadjuvant setting reinforces the need for a better understanding of the neoadjuvant endpoints needed to support regulatory approval.

Despite the fact that pathological complete response (pCR), the most commonly used endpoint in breast cancer neoadjuvant trials, had been proposed as a surrogate endpoint for prediction of long-term clinical benefit, this surrogacy had not been established. To overcome the challenges of interpreting pCR data across clinical trials and to better understand the relationship between pCR and long-term benefit, the US Food and Drug Administration (FDA) established the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) international working group. The CTNeoBC conducted a pooled analysis using primary source data from nearly 12,000 patients enrolled in 12 international neoadjuvant randomized controlled trials.[2] The CTNeoBC pooled analysis showed that eradication of tumor from both the breast and the lymph nodes was more strongly associated with improved long-term outcome than was tumor eradication from the breast alone. Clinical findings from several groups, as discussed by Santa-Maria et al, as well as the CTNeoBC analysis, have demonstrated that the risk of death is reduced for patients who achieve a pCR, supporting the prognostic value of pCR for use in clinical practice. This prognostic value was found to be greatest in patients with aggressive tumor subtypes such as triple-negative, human epidermal growth factor receptor 2 (HER2)-positive, and high-risk hormone receptor–positive/HER2-negative. However, the CTNeoBC pooled analysis showed a weak association between the pCR rate and long-term outcome. Some possible explanations for these findings include tumor heterogeneity, limited targeted therapy, and the small absolute differences in pCR rates between treatment arms in the majority of trials that were included in this pooled analysis.[2] Although the NOAH trial suggested a possible correlation between pCR and long-term outcome, the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) and Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trials showed conflicting results.[3-6] We hope that a future pooled analysis of targeted therapy trials, conducted in more specific breast cancer subtypes with anticipated greater absolute improvements in pCR rates, could help establish pCR as a surrogate endpoint for long-term outcomes.

The FDA recently granted accelerated approval to pertuzumab as the first neoadjuvant treatment for early-stage breast cancer.[7,8] Santa-Maria et al are correct in stating that the approval was based primarily on the NeoSphere trial. However, it is important to emphasize that, given the lack of experience with pCR as a regulatory endpoint and the uncertainty about the association between pCR rate and long-term outcome, the bar for approval in the neoadjuvant setting was set high.[9] Vital to the regulatory decision was the comprehensive clinical development program for pertuzumab, particularly the important improvement in overall survival that was observed in the CLEOPATRA trial.[8,10,11] Furthermore, the adjuvant APHINITY confirmatory trial was fully accrued and well underway at the time of accelerated approval, conforming to the FDA requirement for a post-marketing clinical trial to verify benefit.[12] This comprehensive development program, with a well-characterized safety profile in nearly 10,000 patients who had received pertuzumab, abated the potential risks of accelerated approval.[8]

Biomarker development is another area in which there is much interest in utilizing the neoadjuvant platform. With the advent of next-generation sequencing, new molecular discoveries demonstrating the complexities of breast cancer, and the success of immunotherapy in other malignancies, there is no shortage of potential biomarkers to examine. The neoadjuvant clinical platform allows for a real-time evaluation of biomarkers in the context of the tumor and surrounding microenvironment before, during, and after treatment. Genomic biomarkers are commonly examined in the neoadjuvant setting; this process has included the assessment of genes from multiple pathways, such as the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and the homologous recombination pathway involved in DNA repair.[13-17] In addition, multiple studies have examined the impact of tumor-infiltrating lymphocytes (TILs) as both prognostic and predictive indicators of neoadjuvant treatment response, and many have correlated various measurements of TILs with pCR.[18-24] It is likely, given the interest in immunotherapy, that we will see multiple further assessments of various immune-related biomarkers for the selection of immune therapies in the neoadjuvant setting. Furthermore, assessment of the residual tumor post neoadjuvant therapy could be very useful to identify various mechanisms of drug resistance.

The pathological response to neoadjuvant therapy reflects a complex interaction between the tumor biology, the microenvironment, and systemic therapy. Thus, future innovative neoadjuvant trials that include and validate novel biomarkers are warranted, to identify patients with high-risk early breast cancer-such as those who do not attain a pCR or who, despite achieving a pCR, are destined to relapse. There is no consensus on whether these patients would benefit from additional targeted therapies in the neoadjuvant or adjuvant setting; this is a question to be answered by current ongoing and future trials. Given the complexity of breast cancer, reliable biomarkers that could predict treatment effectiveness have the potential to improve the breast cancer drug development process. Furthermore, tracking the biomarker response during therapy could also allow for a better understanding of the relationship between the biomarker and resistance pathways and/or long-term outcome. Additional breast cancer drug development in the neoadjuvant setting will provide a mechanism for innovative exploration and improvement on the conventional route of drug and biomarker development. We hope that, taken together, these approaches will translate into improved outcomes for our patients with early-stage breast cancer.

Financial Disclosure: The authors have no significant financial relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Santa-Maria CA, Camp M, Cimino-Mathews A, et al. Neoadjuvant therapy for early-stage breast cancer: current practice, controversies, and future directions. Oncology (Williston Park). 2015;29:828-38.

2. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164-72.

3. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633-40.

4. Piccart-Gebhart MJ, Holmes PA, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→ L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). J Clin Oncol. 2014;32(suppl 5s):abstr LBA4.

5. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014;15:640-7.

6. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377-84.

7. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32.

8. Amiri-Kordestani L, Wedam S, Zhang L, et al. First FDA approval of neoadjuvant therapy for breast cancer: pertuzumab for the treatment of patients with HER2-positive breast cancer. Clin Cancer Res. 2014;20:5359-64.

9. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry. Pathologic complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval. October 2014. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm305501.pdf. Accessed October 13, 2015.

10. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-19.

11. Swain SM, Kim SB, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-71.

12. US Food and Drug Administration, Oncologic Drugs Advisory Committee. Meeting announcement. February 8, 2011. http://www.fda.gov/AdvisoryCommittees/Calendar/ucm239360.htm. Accessed October 11, 2015.

13. Loibl S, von Minckwitz G, Schneeweiss A, et al. PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (HER2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol. 2014;32:3212-20.

14. Jiang YZ, Yu KD, Bao J, et al. Favorable prognostic impact in loss of TP53 and PIK3CA mutations after neoadjuvant chemotherapy in breast cancer. Cancer Res. 2014;74:3399-407.

15. Wang C, Zhang J, Wang Y, et al. Prevalence of BRCA1 mutations and responses to neoadjuvant chemotherapy among BRCA1 carriers and non-carriers with triple-negative breast cancer. Ann Oncol. 2015;26:523-8.

16. Telli ML, Jensen KC, Kurian AW, et al. PrECOG 0105: Final efficacy results from a phase II study of gemcitabine (G) and carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer. J Clin Oncol. 2013;31(suppl):abstr 1003.

17. Arun B, Bayraktar S, Liu DD, et al. Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience. J Clin Oncol. 2011;29:3739-46.

18. Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28:105-13.

19. Yamaguchi R, Tanaka M, Yano A, et al. Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer. Hum Pathol. 2012;43:1688-94.

20. West NR, Milne K, Truong PT, et al. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res. 2011;13:R126.

21. Issa-Nummer Y, Darb-Esfahani S, Loibl S, et al. Prospective validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer--a substudy of the neoadjuvant GeparQuinto trial. PLoS One. 2013;8:e79775.

22. Ladoire S, Arnould L, Apetoh L, et al. Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells. Clin Cancer Res. 2008;14:2413-20.

23. Ladoire S, Mignot G, Dabakuyo S, et al. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol. 2011;224:389-400.

24. Aruga T, Suzuki E, Saji S, et al. A low number of tumor-infiltrating FOXP3-positive cells during primary systemic chemotherapy correlates with favorable anti-tumor response in patients with breast cancer. Oncol Rep. 2009;22:273-8.